Водовозова Елена Львовна

Личная информация

Е. Л. Водовозова в 1981 г. поступила в аспирантуру ИБХ РАН. В 1985 г. она защитила диссертацию на степень кандидата химических наук по специальности «биохимия» в области синтеза и применения фотореактивных липидных зондов, тогда еще нового и малоразработанного направления исследований. Работа была выполнена в лаборатории химии липидов. С тех пор она сотрудник этой лаборатории. После защиты докторской диссертации (2007 г.), посвященной разработке новых фотоаффинных липидных зондов для структурно-биологических исследований, Е. Л. Водовозова руководит лабораторией химии липидов.

Образование

Период обученияСтрана, городУчебное заведениеДополнительная информация
1976–1981 Россия, Москва Московский государственный университет имени М.В. Ломоносова (МГУ), химический факультет Диплом химика
1981–1985 Россия, Москва Институт биоорганической химии имени М.М. Шемякина АН СССР (ИБХ) Диплом кандидата химических наук по специальности «биохимия»
2007 Россия, Москва Институт биоорганической химии им. академиков М.М. Шемякина и Ю.А. Овчинникова РАН (ИБХ) Диплом доктора химических наук

Научные интересы

Более 10 лет одним из главных направлений работы Е. Л. Водовозовой являются исследования в области создания систем направленной доставки лекарств на основе липосом, липидных производных противоопухолевых химиотерапевтических средств (липофильных пролекарств) и липофильных гликоконъюгатов (молекулярных адресов). Другое направление исследований, которое развивает Е. Л. Водовозова — это разработка фотоаффинных зондов с новым высокоэффективным фотофором (диазоциклопентадиен-2-илкарбонильной меткой).

Основные научные результаты

В сотрудничестве с отечественными и зарубежными учеными изучена топография цитохрома Р450 в мембране, получены сведения, важные для понимания механизма сборки рецептора интерлейкина-2 в активированных Т-лимфоцитах, определены фрагменты молекулы интерлейкина-4, взаимодействующие с ганглиозидом GM1.

Е. Л. Водовозова — автор 37 публикаций в отечественных и зарубежных журналах, 32 опубликованных тезисов докладов на конференциях в России и за рубежом, главы в монографии и патента.

Избранные публикации

  1. Alekseeva A.A., Moiseeva E.V., Onishchenko N.R., Boldyrev I.A., Singin A.S., Budko A.P., Shprakh Z.S., Molotkovsky J.G., Vodovozova E.L. (2017). Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma. Int J Nanomedicine 12, 3735–3749 [+]

    In a previous study, a formulation of methotrexate (MTX) incorporated in the lipid bilayer of 100-nm liposomes in the form of diglyceride ester (MTX-DG, lipophilic prodrug) was developed. In this study, first, the interactions of MTX-DG liposomes with various human and mouse tumor cell lines were studied using fluorescence techniques. The liposomes composed of egg phosphatidylcholine (PC)/yeast phosphatidylinositol/MTX-DG, 8:1:1 by mol, were labeled with fluorescent analogs of PC and MTX-DG. Carcinoma cells accumulated 5 times more MTX-DG liposomes than the empty liposomes. Studies on inhibitors of liposome uptake and processing by cells demonstrated that the formulation used multiple mechanisms to deliver the prodrug inside the cell. According to the data from the present study, undamaged liposomes fuse with the cell membrane only 1.5-2 hours after binding to the cell surface, and then, the components of liposomal bilayer enter the cell separately. The study on the time course of plasma concentration in mice showed that the area under the curve of MTX generated upon intravenous injection of MTX-DG liposomes exceeded that of intact MTX 2.5-fold. These data suggested the advantage of using liposomal formulation to treat systemic manifestation of hematological malignancies. Indeed, the administration of MTX-DG liposomes to recipient mice bearing T-cell leukemic lymphoma using a dose-sparing regimen resulted in lower toxicity and retarded lymphoma growth rate as compared with MTX.

    ID:1796
  2. German S.V., Navolokin N.A., Kuznetsova N.R., Zuev V.V., Inozemtseva O.A., Aniskov A.A., Volkova E.K., Bucharskaya A.B., Maslyakova G.N., Fakhrullin R.F., Terentyuk G.S., Vodovozova E.L., Gorin D.A. (2015). Liposomes loaded with hydrophilic magnetite nanoparticles: Preparation and application as contrast agents for magnetic resonance imaging. Colloids Surf B Biointerfaces 135, 109–15 [+]

    Magnetic fluid-loaded liposomes (MFLs) were fabricated using magnetite nanoparticles (MNPs) and natural phospholipids via the thin film hydration method followed by extrusion. The size distribution and composition of MFLs were studied using dynamic light scattering and spectrophotometry. The effective ranges of magnetite concentration in MNPs hydrosol and MFLs for contrasting at both T2 and T1 relaxation were determined. On T2 weighted images, the MFLs effectively increased the contrast if compared with MNPs hydrosol, while on T1 weighted images, MNPs hydrosol contrasting was more efficient than that of MFLs. In vivo magnetic resonance imaging (MRI) contrasting properties of MFLs and their effects on tumor and normal tissues morphology, were investigated in rats with transplanted renal cell carcinoma upon intratumoral administration of MFLs. No significant morphological changes in rat internal organs upon intratumoral injection of MFLs were detected, suggesting that the liposomes are relatively safe and can be used as the potential contrasting agents for MRI.

    ID:1421
  3. Alekseeva A., Kapkaeva M., Shcheglovitova O., Boldyrev I., Pazynina G., Bovin N., Vodovozova E. (2015). Interactions of antitumour Sialyl Lewis X liposomes with vascular endothelial cells. Biochim. Biophys. Acta 1848 (5), 1099–1110 [+]

    Recently, we showed that tetrasaccharide selectin ligand SiaLe(X) provided targeted delivery of liposomes loaded in the bilayer with melphalan lipophilic prodrug to tumour endothelium followed by severe injury of tumour vessels in a Lewis lung carcinoma model. Here, we study the impact of SiaLe(X) ligand on the interactions of liposomes with human umbilical vein endothelial cells (HUVEC) using flow cytometry, spectrofluorimetry and confocal microscopy. Liposomes composed of egg phosphatidylcholine/yeast phosphatidylinositol/1,2-dioleoyl glycerol ester of melphalan, 8:1:1, by mol, and varying percentages of lipophilic SiaLe(X) conjugate were labelled with BODIPY-phosphatidylcholine. The increase in SiaLe(X) content in liposomes led to a proportional increase in their uptake by cytokine-activated cells as opposed to non-activated HUVEC: for 10% SiaLe(X) liposomes, binding avidity and overall accumulation increased 14- and 6-fold, respectively. The early stages of intracellular traffic of targeted liposomes in the activated cells were monitored by co-localisation with the trackers of organelles. Endocytosis of SiaLe(X) liposomes occurred mostly via clathrin-independent pathways, which does not contradict the available literature data on E-selectin localisation in the plasma membrane. Using dual fluorescence labelling, with rhodamine-labelled phospholipid and calcein encapsulated at self-quenching concentrations, we found that SiaLe(X) liposomes undergo rapid (within minutes) internalisation by activated HUVEC accompanied by the disruption of liposomes; non-activated cells consumed a negligible dose of liposomes during at least 1.5h. Our data evidence the selective effect of SiaLe(X) formulations on activated endothelial cells and indicate their potential for intracellular delivery of melphalan lipophilic prodrug.

    ID:1242
  4. Privalova A.M., Uglanova S.V., Kuznetsova N.R., Klyachko N.L., Golovin Yu.I., Korenkov V.V., Vodovozova E.L., Markvicheva E.A. (2015). Microencapsulated Multicellular Tumor Spheroids as a Tool to Test Novel Anticancer Nanosized Drug Delivery Systems In Vitro. J. Nanosci. Nanotechnol. 15 (7), 4806–4814 [+]

    In the study, MCF-7 human breast adenocarcinoma cells were used to study cytotoxicity of novel anticancer nanosized formulations, such as docetaxel-loaded nanoemulsion and liposomal formulation of a lipophilic methotrexate (MTX) prodrug. In Vitro study of cytotoxicity was carried out in 2 models, namely using 3D In Vitro model based on multicellular tumor spheroids (MTS) and 2D monolayer culture. MTS were generated by tumor cell cultivation within alginate-oligochitosanmicro-capsules. In the case of the monolayer culture, cell viability was found to be 25, 18 and 12% for the samples containing nanoemulsion at concentrations 20, 300 and 1000 nM of docetaxel, respectively, after 48 hs incubation. For MTS these values were higher, namely 33, 23 and 18%, respectively. Cytotoxicity of liposomal MTX prodrug-based formulation with final concentration of 1, 2, 10, 50, 100 and 1000 nM in both models was also studied. MTX liposomal formulation demonstrated lower cytotoxicity on MTS compared to intact MTX. Moreover, MTS were also more resistant to both liposomal formulation and intact MTX than the monolayer culture. Thus, at 1000 nM MTX in the liposomal form, cell viability in MTS was 1.4-fold higher than that in the monolayer culture. MTS could be proposed as a promising tool to test novel anticancer nanosized formulations In Vitro.

    ID:1142
  5. Alekseeva A.S., Korotaeva A.A., Samoilova E.V., Volynsky P.E., Vodovozova E.L., Boldyrev I.A. (2014). Secretory phospholipase A2 activity in blood serum: The challenge to sense. Biochem. Biophys. Res. Commun. 454 (1), 178–182 [+]

    Excess levels of secretory phospholipase A2 (sPLA2) is known to contribute to several inflammatory diseases including vascular inflammation correlating with coronary events in coronary artery disease. Thus a method to monitor sPLA2 activity in blood serum is urgently needed. Such method is still a challenge since existing fluorescent probes do not allow to monitor sPLA2 activity directly in blood serum. Here we analyze and overcome barriers in sPLA2 sensing methodology and report a fluorescent probe and a kinetic model of its hydrolysis by sPLA2. New probe is designed with a fluorophore and a quencher not interfering binding to the enzyme. At the same time phospholipid matrix bearing the probe promotes efficient initial quenching of the fluorophore. Kinetic model of probe hydrolysis takes into account signal change due to the side processes. The probe and the kinetic model applied together prove the concept that the activity of sPLA can be measured directly in blood serum.

    ID:1124
  6. Vlasenko Yu.V., Alekseeva A.S., Vodovozova E.L. (2014). Synthesis of a Fluorescent Analogue of Methotrexate Lipophilic Prodrug. Russ. J. Bioorgan. Chem. 40 (1), 114–117 [+]
    A fluorescent analogue of the lipophilic prodrug of antitumor agent methotrexate has been synthesized. The conjugate consists of a residue of rac 1 [13 (Me 4 BODIPY 8)tridecanoyl] 2 oleoylglycerol connected to methotrexate by an ester bond via β Ala N carbonylmethylene linker (Me 4 BODIPY 8 stands for 4,4 difluoro 1,3,5,7 tetramethyl 4 bora 3a,4a diaza s indacene 8 yl). The probe is designed for incor poration in the membrane of the liposomal vehicle to study a mechanism of interaction with tumor cells and intracellular traffic.
    ID:1001
  7. Kuznetsova N.R., Stepanova E.V., Peretolchina N.M., Khochenkov D.A., Boldyrev I.A., Bovin N.V., Vodovozova E.L. (2014). Targeting liposomes loaded with melphalan prodrug to tumour vasculature via the Sialyl Lewis X selectin ligand. J Drug Target 22 (3), 242–250 [+]

    Earlier we showed that liposome formulation of DL-melphalan lipophilic prodrug bearing tetrasaccharide Sialyl Lewis X (SiaLe(X)) caused prolonged therapeutic effect on mammary cancer in mice. Here, we compare antivascular effect of SiaLe(X)-liposomes loaded with diglyceride ester of melphalan (Mlph) against SiaLe(X)-free formulation in Lewis lung carcinoma model. Methods: Liposomes of egg phosphatidylcholine/yeast phosphatidylinositol/1,2-dioleoyl glycerol (DOG) conjugate of Mlph/±SiaLe(X)-PEG8-15-DOG, 8:1:1:0.2 by mol, were prepared by standard extrusion. After two intravenous injections with Mlph or liposomes under either standard or delayed treatment protocols, vascular-disrupting effects of the preparations were evaluated basing on tumour section histomorphology, lectin perfusion assay and immunohistochemistry (anti-CD31 staining) data. Also, untreated mice were administered with fluorescently-labelled liposomes to assess their distribution in tumour sections with confocal laser scanning microscopy. Results: Two injections of SiaLe(X)-liposomes reproducibly caused severe injuries of tumour vessels. SiaLe(X)-liposomes co-localized with CD31 marker on vascular endothelium while the non-targeted formulation extravasated into tumour. Discussion: Cytotoxic SiaLe(X)-liposomes exhibit superior vascular-disrupting properties compared to non-targeted liposomes, yet the effect starts to transform into gain in tumour growth inhibition only under delayed treatment regimen. Conclusion: SiaLe(X)-ligand provides targeting of cytotoxic liposomes to tumour endothelium and subsequent antivascular effect.

    ID:997
  8. Kuznetsova N.R., Svirshchevskaya E.V., Skripnik I.V., Zarudnaya E.N., Benke A.N., Gaenko G.P., Molotkovskiĭ Yu.G., Vodovozova E.L. (2013). Interaction of liposomes bearing a lipophilic doxorubicin prodrug with tumor cells. Biochemistry (Moscow) Supplement Series A: Membrane and Cell Biology 7 (1), 12–20 [+]

    When used as nanosized carriers, liposomes enable targeted delivery and decrease systemic toxicity of antitumor agents significantly. However, slow unloading of liposomes inside cells diminishes the treatment efficiency. The problem could be overcome by the adoption of lipophilic prodrugs tailored for incorporation into lipid bilayer of liposomes. We prepared liposomes of egg yolk phosphatidylcholine and yeast phosphatidylinositol bearing a diglyceride conjugate of an antitumor antibiotic doxorubicin (a lipophilic prodrug, DOX-DG) in the membrane to study how these formulations interact with tumor cells. We also prepared liposomes of rigid bilayer-forming lipids, such as a mixture of dipalmitoylphosphatidylcholine and cholesterol, bearing DOX in the inner water volume, both pegylated (with polyethylene glycol (PEG) chains exposed to water phase) and non-pegylated. Efficiency of binding of free and liposomal doxorubicin with tumor cells was evaluated in vitro using spectrofluorimetry of cell extracts and flow cytometry. Intracellular traffic of the formulations was investigated by confocal microscopy; co-localization of DOX fluorescence with organelle trackers was estimated. All liposomal formulations of DOX were shown to distribute to organelles retarding its transport to nucleus. Intracellular distribution of liposomal DOX depended on liposome structure and pegylation. We conclude that the most probable mechanism of the lipophilic prodrug penetration into a cell is liposome-mediated endosomal pathway.

    ID:996
  9. Krasnov V.P., Korolyova M.A., Vodovozova E.L. (2013). Nano-sized melphalan and sarcolysine drug delivery systems: synthesis and prospects of application. Russian Chemical Reviews 82 (8), 783–814 [+]

    The results of experimental studies concerned with the development of nano-sized drug delivery systems for the antitumour drugs sarcolysine and melphalan are generalized. The structures and biological activities of nanocarriers in comparison with unmodified drugs are discussed. Particular attention is given to the liposomes containing lipid derivatives of sarcolysine and melphalan in the lipid bilayer.

    ID:1002
  10. Kuznetsova N.R., Sevrin C., Lespineux D., Bovin N.V., Vodovozova E.L., Mészáros T., Szebeni J., Grandfils C. (2011). Hemocompatibility of liposomes loaded with lipophilic prodrugs of methotrexate and melphalan in the lipid bilayer. Journal of controlled release : official journal of the Controlled Release Society , [+]

    A panel of in vitro tests intended for evaluation of the nano-sized drug delivery systems' compliance with human blood was applied to liposomal formulations of anticancer lipophilic prodrugs incorporated into the lipid bilayer. Liposomes on the basis of natural phosphatidylcholine (PC) and phosphatidylinositol (PI), 8:1 (mol) were loaded with 10mol% of either methotrexate or melphalan 1,2-dioleoylglyceride esters (MTX-DOG and Mlph-DOG respectively) and either decorated with 2mol% of sialyl Lewis X/A (SiaLe(X/A)) tetrasaccharide ligand or not. Hemolysis rate, red blood cells and platelets integrity and size distribution, complement (C) activation, and coagulation cascade functioning were analyzed upon the material incubation with whole blood. Both formulations were negatively charged with the zeta potential value being higher in the case of MTX-DOG liposomes, which also were larger than Mlph-DOG liposomes and more prone to aggregation. Accordingly, in hemocompatibility tests Mlph-DOG liposomes did not provoke any undesirable effects, while MTX-DOG liposomes induced significant C activation and abnormal coagulation times in a concentration-dependent manner. Reactivity of the liposome surface was not affected by the presence of SiaLe(X/A) or PI. Decrease in liposome loading with MTX-DOG from 10 to 2.5% resulted in lower surface charge density, smaller liposome size and considerably reduced impact on C activation and coagulation cascades.

    ID:644
  11. Moiseeva E.V., Kuznetsova N.R., Svirshchevskaya E.V., Bovin N.V., Sitnikov N.S., Shavyrin A.S., Beletskaya I.P., Combes S., Fedorov A.Y.u., Vodovozova E.L. (2011). Liposome formulations of combretastatin A4 and its 4-arylcoumarin analogue prodrugs: The antitumor effect in the mouse model of breast cancer. Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry 5 (3), 276–283 [+]

    The antimitotic agent combretastatin A-4 (CA-4) has been recently proposed as an antivascular agent for anticancer therapy. In order to reduce systemic toxicity by means of administration in liposome formulations, new lipophilic prodrugs, oleic derivatives of CA-4 and its 4-arylcoumarin analogue (CA4-Ole and ArC-Ole, respectively), have been synthesized in this study. Liposomes with mean diameter of 100 nm prepared on the basis of egg phosphatidylcholine and baker’s yeast phosphatidylinositol quantitatively included up to 15 mol% of CA4-Ole, or 7 mol% of ArC-Ole. To achieve targeting to neovascular endothelium prodrug bearing liposomes decorated with the tetrasaccharide selectin ligand Sialyl Lewis X (SiaLeX) have been also prepared. The antitumor activity was studied in vivo using the model of slow-growing mouse breast cancer. Under the dose used (22 mg/kg) and the administration protocol (four injections, one per a week, starting from the appearance of palpable tumors) cytostatic CA-4 did not reveal any anticancer effect; moreover, it even stimulated tumor growth. The liposome formulations of CA4-Ole did not demonstrate such stimulation. However, to achieve a pronounced antitumor effect, the number of injections of liposomes should be apparently increased. The cytotoxic activity of a novel antimitotic agent ArC was one order of magnitude lower in the human breast carcinoma cell culture in vitro. Nevertheless, in vivo in the mouse model of breast cancer the antitumor effect of this compound corresponded to the double equivalent dose of CA-4. The results demonstrate perspectives of SiaLeX-liposomes loaded with ArC-Ole: the preparation partially inhibited tumor growth already after the second injection. Thus, subsequent optimization of doses and regimens of administration both for ArC and liposomal ArC-Ole formulations are needed.

    ID:671
  12. Vodovozova E.L., Pazynina G.V., Bovin N.V. (2011). Synthesis of diglyceride conjugate of selectin ligand SiaLeX as a vector for targeting of drug-loaded liposomes. Mendeleev Communications 21 (2), 69–71 [+]

    A conjugate of tetrasaccharide Sialyl Lewis X [SiaLeX, Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ] 3-aminopropyl glycoside and rac-1,2-dioleoyl-3-carboxymethylene[poly(8–15)oxyethylene]oxyacetylamidopropionylglycerol amenable for the incorporation in lipid bilayer of drug-loaded liposomes to achieve targeting in tumors and inflammation foci was obtained by the formation of carboxamide bond.

    ID:670
  13. Tsoy A., ZaytsevaZotova D., Edelweiss E., Bartkowiak A., Goergen J.L., Vodovozova E., Markvicheva E. (2010). Microencapsulated multicellular tumor spheroids as a novel in vitro model for drug screening. Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry 4 (3), 243–250 [+]

    В работе использован метод микрокапсулирования  клеток аденокарциномы молочной железы человека MCF-7 в биосовместимые альгинат-хитозановые микрокапсулы с целью генерирования на основе этих клеток  мультиклеточных опухолевых сфероидов (МОС)  и их дальнейшего исследования в качестве модели in vitro для тестирования противораковых лекарственных средств. На МОС, полученных на основе клеточной линии MCF-7 (аденокарцинома молочной железы человека), было исследовано цитотоксическое действие метотрексата. В зависимости от времени культивирования клеток в микрокапсулах были  получены МОС со средним размером 150, 200 и 300 мкм. После инкубирования МОС с метотрексатом различных концентраций (1, 2, 10, 50 и 100 нМ) в течение 48 часов оценивали количество жизнеспособных клеток. Показано, что МОС гораздо устойчивее к метотрексату, чем монослойная культура. Так, при концентрации метотрексата 100 нМ в МОС размером 300 мкм доля жизнеспособных клеток в 2,5 раза превышала количество живых клеток в монослойной культуре. Таким образом, было показано, что микрокапсулированные  МОС могут более адекватно отражать состояние клеток  в малых солидных опухолях, чем монослойная культура,  и могут в дальнейшем быть предложены в качестве новой модели in vitro для тестирования противораковых лекарств.

    ID:372
  14. Kuznetsova N., Kandyba A., Vostrov I., Kadykov V., Gaenko G., Molotkovsky J., Vodovozova E. (2009). Liposomes loaded with lipophilic prodrugs of methotrexate and melphalan as convenient drug delivery vehicles. J. Drug. Deliv. Sci. Techn. 19, 51–59 [+]

    Liposomal formulations prepared by extrusion from natural phospholipids and 1,2-dioleoylglycerol conjugates of methotrexate and melphalan (egg phosphatidylcholine–phosphatidylinositol–prodrug, 8:1:1, by mol.) were characterized by size, composition and stability. Both prodrugs were shown to incorporate completely into unilamellar liposomes with the mean size below 100 nm and form stable dispersions containing the drug concentrations relevant for systemic injections in animals. For long-term storage, the dispersions can be  subjected to deep freezing (- 196°C) and stored at - 70°C; before usage, they should be defrosted and treated shortly in an ultrasonic bath. According to the example of methotrexate conjugate, stability of prodrug ester bond in liposomal formulation towards hydrolysis by human plasma esterases during 24-h incubation were established. Also, liposomes bearing methotrexate conjugate were shown to overcome resistance of human leukemia cells related to impaired transport of initial drug across the membrane.

    ID:106
  15. Vodovozova E.L., Pazynina G.V., Tuzikov A.B., Grechishnikova I.V., Molotkovsky J.G. (2009). Synthesis of photoreactive inorganic probes--instruments for studying membrane lectins. Bioorg. Khim. 30 (2), 174–81 [+]

    A method for the synthesis of photoaffinity neoglycolipid probes with a highly efficient carbene-generating diazocyclopentadien-2-ylcarbonyl (Dcp) label, which can be radioiodinated under standard oxidation conditions, was developed. The probes are intended for incorporation into the lipid bilayer. They are lipophilic glycoconjugates on the basis of an amphiphilic aglycone built up from a diacylglycerol and a polyethylene glycol spacer (with a polymerization degree of 9-16) bearing the Dcp label at the terminal unit. The location of the label in the aglycone provides the possibility of one-step preparation of a wide range of probes using various carbohydrate synthons. We have synthesized photoaffinity neoglycoconjugates containing the oligosaccharides: sialyl LewisX tetrasaccharide and A trisaccharide, which is specific to some tumor cells. A probe containing an inactive pentaol (aminodeoxyglucitol) was also synthesized to detect nonspecific binding. The Dcp label is bound to the probe molecule by ester bond; its lability under alkaline conditions facilitates the analysis of cross-linked products after photoaffinity labeling. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 2; see also http://www.maik.ru.

    ID:242
  16. Vodovozova E.L., Tsibizova E.V., Molotkovsky J.G. (2001). One-step iodination of the diazocyclopentadien-2-ylcarbonyl group—a new and convenient preparation of effective radiolabelled photoaffinity probes. J. Chem. Soc., Perkin Trans. 1  (200), 2221–2228 [+]

    A detailed study devoted to direct iodination of the photoactivatable diazocyclopentadien-2-ylcarbonyl (Dcp) group is presented. The iodination does not influence the high carbene reactivity of the Dcp-generated carbene. It was shown that the Dcp substituent forms 4-mono-, 5-mono- and 4,5-diiododerivatives upon iodination under oxidative conditions (76, 20 and 4%, respectively, when DcpOMe 2 is iodinated). Photolysis of the individual products of iodination in cyclohexane resulted in rather high insertion into non-activated CH bonds, without noticeable loss of iodine. Syntheses of new phospholipid and ganglioside membrane probes are also described which incorporate the Dcp function via a labile ester bond. A [125I]-Dcp-phosphatidylcholine probe exhibiting high specific radioactivity (∼500 Ci mmol1) was easily prepared at yields of 90% (on the starting Na125I), by using peracetic acid as an oxidant.
    Furthermore, it was successfully used for photolabelling of the integral protein hemagglutinin in a well-characterised influenza virus model. In summary, the Dcp group is efficient for labelling a wide variety of molecules, and as such, it provides a new tool for exploring a diverse range of biological systems.

    ID:182
  17. Vodovozova E.L., Moiseeva E.V., Grechko G.K., Gayenko G.P., Nifant'ev N.E., Bovin N.V., Molotkovsky J.G. (2000). Antitumour activity of cytotoxic liposomes equipped with selectin ligand SiaLe(X), in a mouse mammary adenocarcinoma model. Eur. J. Cancer 36 (7), 942–9 [+]

    The overexpression of lectins by malignant cells compared with normal ones can be used for the targeting of drug-loaded liposomes to tumours with the help of specific carbohydrate ligands (vectors). Recently we have shown that liposomes bearing specific lipid-anchored glycoconjugates on a polymeric matrix bind in vitro to human malignant cells more effectively and, being loaded with a lipophilic prodrug of merphalan, reveal higher cytotoxic activity compared with unvectored liposomes. In this study, carbohydrate-equipped cytotoxic liposomes were tested in vivo in a mouse breast cancer model, BLRB-Rb (8.17)1Iem strain with a high incidence of spontaneous mammary adenocarcinoma (SMA). Firstly, a cell line of the SMA was established which was then used to determine the specificity of the tumour cell lectins. After screening of the lectin specificity of a number of fluorescent carbohydrate probes, SiaLe(X) was shown to be the ligand with the most affinity, and a lipophilic vector bearing this saccharide was synthesised. Then different liposomal formulations of the synthetic merphalan lipid derivative and SiaLe(X) vector were prepared and applied in the treatment of mice with grafted adenocarcinomas. The results of the tumorigenesis data show that the therapeutic efficacy of merphalan increases sharply after its insertion as a lipophilic prodrug into the membrane of SiaLe(X)-vectored liposomes.

    ID:109
  18. Vodovozova E.L., Gayenko G.P., Razinkov V.I., Korchagina E.Y., Bovin N.V., Molotkovsky J.G. (1998). Saccharide-assisted delivery of cytotoxic liposomes to human malignant cells. Biochem. Mol. Biol. Int. 44 (3), 543–53 [+]

    The overexpression of lectins by malignant cells was applied for in vitro targeting of liposomes equipped with a saccharide vector and loaded in the lipid phase with a lipid derivative of anticancer agent sarcolysine. The lectin specificity of human leukemia HL-60 and human lung adenocarcinoma ACL cells was revealed by tests with fluorescein-labeled sugar probes. With the help of fluorescent lipid dye it was shown that active saccharide ligands increased the level of the vectored liposome binding to malignant cells by 50-80% as compared to liposomes without vector or with inactive one. The degree of liposome/cell membrane fusion was monitored fluorometrically and was shown to be complete and independent of the vectors. The targeted drug-loaded liposomes had the cytotoxic activity 2-4 times higher as compared to the vector-free ones.

    ID:110
  19. Martynova M.A., Manevich E.M., Vodovozova E.L., Muzia G.I., Bezuglov V.V. (1988). [Interaction of prostaglandins with low-density lipoproteins in human blood]. Biokhimiia 53 (5), 721–7 [+]

    Interaction of prostaglandins (PG) with human plasma low density lipoproteins (LDL) was studied, using fluorescent spectroscopy and photoreactive labeling. It was demonstrated that PGE1 at low concentrations (less than 10(-9) M) induces specific lipid rearrangements on the surface of LDL globules. It was assumed that these rearrangements are brought about by the interaction of PG with apolipoprotein B to form short-living complexes. A possible mechanism and biological significance of the observed phenomenon are discussed.

    ID:629